Effects of BMY 33462, a selective and potent serotonin type‐3 receptor antagonist, on mesolimbic dopamine‐mediated behavior

The compound BMY 33462 (4‐amino‐N‐(1‐azabicyclo‐[2,2,2]oct‐3‐yl)‐2‐(butan‐2‐one‐3‐yl)oxy‐5‐chlorobenzamine 1.25 fumerate hydrate) has been shown to be a selective and potent serotonin type‐3 (5‐HT 3 ) receptor antagonist. Its receptor binding profile includes subnanomolar affinity for the 5‐HT 3 receptor (K i , 0.22 ± 0.06 nM) and no affinity for other serotonergic, dopaminergic, and adrenergic receptors (K i > 1,000 nM). BMY 33462 was also shown to be a potent inhibitor of the Bezold‐Jarisch reflex in the anesthetized rat (ED 50 , 0.09 μg/kg, iv), a functional correlate of 5‐HT 3 receptor antagonism in vivo. It has been reported that ondansetron and other 5‐HT 3 antagonists have the ability to block hyperactivity in rats induced by DiMe‐C7 ([pGlu 5 , Me‐Phe 8 , Sar 9 ]SP 5–11 ), a metabolically stable analogue of substance P [Hagan et al. (1990): Br J Pharmacol 99:227–232]. DiMe‐C7‐induced hyperactivity is thought to occur through activation of mesolimbic dopamine (DA) neurons which project to the nucleus accumbens [West and Michael (1991): Brain Res Bull 26:229–233]. BMY 33462 was examined for its ability to block DiMe‐C7‐induced hyperactivity as was haloperiodol and ondansetron. The dopamine‐2 (D 2 ) antagonist haloperidol produced the greatest inhibition of DiMe‐C7‐induced hyperactivity at a dose of 0.025 mg/kg (53.7%). Ondansetron significantly inhibited the DiMe‐C7‐induced increase in locomotor activity at doses of 0.10 mg/kg and 0.50 mg/kg (42% and 30%, respectively). BMY 33462, at doses of 0.025 mg/kg and 0.05 mg/kg, significantly decreased DiMe‐C7‐induced hyperactivity by 41% and 37%, respectively. Haloperidol proved to be highly efficacious and potent in blocking increases in DiMe‐C7‐induced locomotor activity, a phenomenon which may correlate with its clinical effectiveness as a neuroleptic agent. BMY 33462 and ondansetron were equally efficacious, however, BMY 33462 was more potent. The ability of 5‐HT 3 antagonists to alter a mesolimbic DA‐mediated behavior indicates a complex interaction between these two neurotransmitter systems and perhaps a role for central 5‐HT 3 receptors and 5‐HT in the regulation of DA transmission. In addition, BMY 33462 and ondansetron were unable to inhibit stereotypy induced by apomorphine (inactive at 100 mg/kg, orally) suggesting a lack of interaction with the nigrostriatal DA pathway. These results support the notion that 5‐HT 3 antagonists may be potential therapeutic agents for the treatment of hyperdopaminergic disease states, such as schizophrenia, without the side effect liability generally associated with classical neuroleptics. © 1993 Wiley‐Liss, Inc.